The long term objective of this researrch is to determine the mechanism of radiation carcinogenesis using an in vitro transformation system. The specific objectives of the current grant involve studies of two-stage transformation in vitro using a low dose of radiation as the initiating agent and various steroid hormones as promoting agents. We propose to perform experiments to determine: 1) when during the transformation assay hormones can be applied to enhance radiation transformation and whether steroid hormones affect the growth patterns of irradiated cells; 2) whether steroid hormones other than those we have already studied (cortisone, dexamethasone and 17-Beta-estradiol) affect radiation-induced transformation in vitro; 3) whether estrogen antagonists or antiestrogens will inhibit 17-Beta-estradiol enhanced radiation transformation in vitro; 4) whether protease inhibitors, with emphasis on those present in the normal diet which show promise as cancer chemopreventive agents, can inhibit radiation-steroid hormone enhanced transformation in vitro; whether the enhancing effects of steroid hormones on x-ray induced malignant transformation are associated with characteristic changes in the pattern of steroid binding to nuclear and/or cytoplasmic binding sites. As part of these studies, we propose to study whether protease inhibitors affect steroid binding patterns in a manner consistent with our previous observation that the protease inhibitors antipain and leupeptin could suppress transformation in vitro induced by x-radiation and 17-Beta-estradiol. These binding and in vitro transformation studies will be performed with C3H 10T1/2 cells, a mouse embryo derived cell line used extensively in """"""""two-stage"""""""" in vitro transformation research. These studies should help to elucidate the mechanism of steroid hormone interactions with radiation in the development of transformation in vitro.
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